Bioinformatics-Guided In Vitro Method to Demonstrate the Inhibition

Latin American Journal of Pharmacy
(formerly Acta Farmacéutica Bonaerense)
Lat. Am. J. Pharm. 34 (5): 1047-50 (2015)
Short communication
Received: March 20, 2015
Accepted: March 23, 2015
Bioinformatics-Guided In Vitro Method to Demonstrate
the Inhibition of Cardiovascular Drug
(R)-Rivaroxaban towards Cytochrome P450 (CYP) 3A4
Pei SHI, Ling LI * & Zhongle BAI
Department of Cardiovascular Medicine, The First Affiliated Hospital
of Zhengzhou University, Zhengzhou 450052, China
SUMMARY. The present study aims to investigate the inhibition behavior of (R)-rivaroxaban towards of
cytochrome P450 (CYP) 3A4 using bioinformatics-guided in vitro method. Supposed that (R)-rivaroxaban
has similar structure with ketoconazole, the structure of (R)-rivaroxaban was docked into the activity site
of CYP3A4 from which ketoconazole was extracted. From multiple confirmations of (R)-rivaroxaban, the
best orientation exerts close distance (1.85 Å) with the catalytic center of CYP3A4. The amino acids forming the interaction with (R)-rivaroxaban are consisted of Ser119, Thr309, and Phe304, and several hydrogen bonds formed between amino acids and the structures of (R)-rivaroxaban. The co-docking of (R)-rivaroxaban and ketoconazole was carried out, and the results showed that (R)-rivaroxaban has closer distance (1.85 Å) than ketoconazole (2.1Å), indicating that (R)-rivaroxaban is a strong inhibitor. In vitro experiment showed that (R)-rivaroxaban inhibited CYP3A4-catalyzed midazolam metabolism. In conclusion, much attention should be given to the drug-drug interaction between (R)-rivaroxaban and the good
substrates of CYP3A4.
RESUMEN. El presente estudio tiene como objetivo investigar el comportamiento de inhibición de (R)-rivaroxaban hacia el citocromo P450 (CYP) 3A4 utilizando un método in vitro de bioinformática guiada. Dado que (R)rivaroxaban tiene una estructura similar al ketoconazol, (R) -rivaroxaban se ancló en el sitio activode CYP3A4
cuando se extrajo el ketoconazol. De múltiples confirmaciones con (R) -rivaroxaban, la mejor orientación se
ejerce a corta distancia (1,85 Å) con el centro catalítico de CYP3A4. Los aminoácidos que interaccionan con
(R)-rivaroxaban son Ser119, Thr309 y Phe304, con varios enlaces de hidrógeno formados entre los aminoácidos
y las estructuras de (R)-rivaroxaban. También se llevó a cabo el co-acoplamiento de (R)-rivaroxaban y ketoconazol y los resultados mostraron que (R)-rivaroxaban tiene una distancia más cercana (1,85 Å) que el ketoconazol
(2.1 Å), lo que indica que (R)-rivaroxaban es un fuerte inhibidor. Los experimentos in vitro mostraron que el metabolismo de midazolam catalizado por CYP3A4 resulta inhibido por (R)-rivaroxaban. En conclusión, se debe
prestar mucha atención a la interacción fármaco-fármaco entre (R)-rivaroxaban y los buenos sustratos del
CYP3A4.
KEY WORDS: rivaroxaban, enantiomers, cytochrome P450 3A4, docking
*
Author to whom correspondence should be addressed. E-mail: [email protected]
ISSN 0326 2383 (printed ed.)
ISSN 2362-3853 (on line ed.)
1047